Tryptophan is an essential amino acid, serving as the precursor of the neurotransmitter, serotonin, and of the hormone, melatonin, in addition to its role in enzymes and in receptor proteins. Tryptophan is metabolized in mammals by a pyrroloxygenase in the liver, where it can serve as a precursor of nicotinamide (Vitamine B6) in some animals. In other tissues, tryptophan and related indoles are metabolized by a distinct oxygenase, the activity of which is dramatically increased (up to 100-fold) upon administration of bacterial lipopolysaccharides or interferon. The role of this oxygenase in the response of the organism to infection is unknown, however. We anticipated that certain 2-substituted tryptophans might serve as selective "suicide substrates" for these oxygenases, and would therefore be useful research tools. For example, a selective inhibitor of the interferon-induced oxygenase might allow for an evaluation of the role of this enzyme in the response of the organism to infection. Analogs of tryptophan with electronegative substituents at C-2 had not been previously prepared. In the initial phase of this work we have developed synthetic procedures for preparation of 2-chloro-L-tryptophan and 2-bromo-L-tryptophan in good yield. Currently, we are studying the chemical properties of these compounds, particularly their stability in aqueous solution. Initial results indicate excellent stability at physiological pH, but rapid decomposition in acidic media, due to intramolecular catalysis by the side-chain carboxylic acid function. In the course of these studies, we discovered that the hydrolysis product of the 2-halotryptophans, oxindolylalanine, is a potent inhibitor of the bacterial enzymes, trytophanase and tryptophan synthase, possibly due to its action as a transition-state analog. Future experiments will be carried out to determine if these 2-halotryptophans indeed act as "suicide substrates" for the pyrroloxygenases. In addition, we shall attempt the syntheses of the 2-fluoro and 2-azido analogs and plan to extend the halogenation reaction to other indoles of biomedical interest (e.g., serotonin and melatonin).